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Structural insights into proteoglycan-shaped Hedgehog signaling

Hedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determine... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America 08 October 2013, Vol.110(41), pp.16420-5
Main Author: Whalen, Daniel M
Other Authors: Malinauskas, Tomas , Gilbert, Robert J C , Siebold, Christian
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; PMID: 24062467 Version:1 ; DOI: 10.1073/pnas.1310097110
Link: http://pubmed.gov/24062467
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recordid: medline24062467
title: Structural insights into proteoglycan-shaped Hedgehog signaling
format: Article
creator:
  • Whalen, Daniel M
  • Malinauskas, Tomas
  • Gilbert, Robert J C
  • Siebold, Christian
subjects:
  • Models, Molecular
  • Protein Conformation
  • Glycosaminoglycans -- Metabolism
  • Hedgehog Proteins -- Chemistry
  • Proteoglycans -- Metabolism
  • Signal Transduction -- Physiology
ispartof: Proceedings of the National Academy of Sciences of the United States of America, 08 October 2013, Vol.110(41), pp.16420-5
description: Hedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determined crystal structures of Sonic Hh complexes with two GAGs, heparin and chondroitin sulfate. The interaction determinants, confirmed by site-directed mutagenesis and binding studies, reveal a previously not identified Hh site for GAG binding, common to all Hh proteins. The majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Crystal packing analysis, combined with analytical ultracentrifugation of Sonic Hh-GAG complexes, suggests a potential mechanism for GAG-dependent Hh multimerization. Taken together, these results provide a direct mechanistic explanation of the observed correlation between disease and impaired Hh gradient formation....
language: eng
source:
identifier: E-ISSN: 1091-6490 ; PMID: 24062467 Version:1 ; DOI: 10.1073/pnas.1310097110
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleStructural insights into proteoglycan-shaped Hedgehog signaling
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subjectModels, Molecular ; Protein Conformation ; Glycosaminoglycans -- Metabolism ; Hedgehog Proteins -- Chemistry ; Proteoglycans -- Metabolism ; Signal Transduction -- Physiology
descriptionHedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determined crystal structures of Sonic Hh complexes with two GAGs, heparin and chondroitin sulfate. The interaction determinants, confirmed by site-directed mutagenesis and binding studies, reveal a previously not identified Hh site for GAG binding, common to all Hh proteins. The majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Crystal packing analysis, combined with analytical ultracentrifugation of Sonic Hh-GAG complexes, suggests a potential mechanism for GAG-dependent Hh multimerization. Taken together, these results provide a direct mechanistic explanation of the observed correlation between disease and impaired Hh gradient formation....
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descriptionHedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determined crystal structures of Sonic Hh complexes with two GAGs, heparin and chondroitin sulfate. The interaction determinants, confirmed by site-directed mutagenesis and binding studies, reveal a previously not identified Hh site for GAG binding, common to all Hh proteins. The majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Crystal packing analysis, combined with analytical ultracentrifugation of Sonic Hh-GAG complexes, suggests a potential mechanism for GAG-dependent Hh multimerization. Taken together, these results provide a direct mechanistic explanation of the observed correlation between disease and impaired Hh gradient formation....
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abstractHedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determined crystal structures of Sonic Hh complexes with two GAGs, heparin and chondroitin sulfate. The interaction determinants, confirmed by site-directed mutagenesis and binding studies, reveal a previously not identified Hh site for GAG binding, common to all Hh proteins. The majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Crystal packing analysis, combined with analytical ultracentrifugation of Sonic Hh-GAG complexes, suggests a potential mechanism for GAG-dependent Hh multimerization. Taken together, these results provide a direct mechanistic explanation of the observed correlation between disease and impaired Hh gradient formation....
doi10.1073/pnas.1310097110
pmid24062467
date2013-10-08